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GeNeViSTA
| S.cerevisae | H.sapiens
| ||
COMPLEX | SWI/SNF | RSC | BAF | PBAF
|
Swi2/Snf2 | Sth1 | BRG1/hBRM | BRG1 | |
Swi3 | Rsc8/Swh3 | BAF155/BAF170
| ||
Swi1/Adr6 | BAF250 a,b | |||
Rsc9 | BAF200 | |||
Rsc1,2,4 | BAF180 | |||
Swp73 | Rsc6 | BAF60 a,b,c
| ||
Snf5 | Sfhl | INI1/BAF47/hSNF5
| ||
BAF57
| ||||
BAF45 a,b,C,d
| ||||
Arp7,9 | Beta actin
| |||
BAF53a,b
| ||||
BRD7 | ||||
Swp82 | ||||
Snf6 | ||||
Snf11 | ||||
Taf14 | ||||
Rsc3-5,7 | ||||
Rsc10,30 | ||||
Ht11 | ||||
Ldb7 | ||||
SWI/SNF complex consists of 15–20 subunits and is thought to remodel chromatin through ATP-dependent sliding of nucleosomes along the DNA. It binds near promoters to facilitate the binding of transcription factors and regulate the expression of genes in yeast, including those involved in sugar and iron uptake. In humans, its mode of action is less clear. Many SWI/SNF complexes do not bind near promoter sites, but a substantial number of genes involved in cellular processes are controlled by this complex, like those involved in cell adhesion and cell differentiation. The catalytic subunits of SWI/SNF complex, the SMARCA2 and SMARCA4 ATPases, as well as structural components, ARID1A and ARID1B, are required for transcription regulation. Moreover, these subunits can exert antagonistic effects on transcription regulation of cell cycle regulators, like c-Myc, illustrating their importance in determining SWI/SNF activity. It has been shown that the structure of the complex changes upon differentiation of cells, suggesting that distinct SWI/SNF complex may be important for cell differentiation. SWI/SNF also plays important role in DNA repair. Its inactivation leads to impaired DNA repair and reduced cell survival after exposure to genotoxic agents. Defects in DNA repair often lead to genomic instability, which is one of the hallmarks of cancer. This explains why inactivating mutations in SWI/SNF components results in genomic instability and could lead to cancer development.
Chromatin remodeling is an enzyme-mediated process which facilitates access of nucleosomal DNA by remodeling the structure, composition and positioning of nucleosomes. Nucleosomal DNA is accessed by two major classes of protein complexes: 1) Covalent histone-modifying complexes, 2) ATP-dependent chromatin remodeling complexes. Histone-modifying complexes are specific protein complexes that catalyze addition or removal of various chemical elements on histones. These enzymatic modifications include methylation, acetylation, phosphorylation, and ubiquitination and primarily occur at N-terminal histone tails. These enzymatic modifications affect the binding affinity between histones and DNA, and thus, loosening and tightening of the condensed DNA wrapped around histones. ATP-dependent chromatin-remodeling complexes regulate gene expression by either moving, ejecting or restructuring nucleosomes. These chromatin-remodeling complexes have a common ATPase domain. Energy from the hydrolysis of ATP allows these chromatin-remodeling complexes to reposition nucleosomes (slide, twist or loop) along the DNA or remove histone from DNA, or causes exchange of histone variants (Fig. 6). This creates nucleosome-free regions of DNA for gene activation. SWI/SNF is an ATP-dependent nucleosome remodeling complex. Two mechanisms of chromosome remodeling by SWI/SNF have been proposed. The first model involves a unidirectional diffusion of a twist defect in the nucleosomal DNA that starts at the DNA entry site of the nucleosome and results in a corkscrew-like propagation of DNA on the histone octamer surface. The second model involves “loop-recapture” mechanism. It involves the dissociation of DNA from the edge of the nucleosome and reassociation of DNA inside the nucleosome, resulting in a DNA bulge on the octamer surface. The DNA loop then propagates over the surface of the histone in a wave-like manner and results in the repositioning of DNA to histone without changes in the total number of DNA-histone contacts. A recent study has concluded strong evidence against the twist diffusion mechanism and has further strengthened the loop-recapture model (Tang et al., 2010).
In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitor cells and postmitotic neurons. Particularly, the neural progenitor-specific BAF (npBAF) complexes are essential for controlling the neural progenitor cell division, while neuronal BAF (nBAF) function is necessary for the maturation of post-mitotic neurons as well as long-term memory formation. Transition from npBAF to nBAF complexes is a microRNA-mediated mechanism and is instructive for the neuronal fate and can even convert fibroblasts into neurons. In neurological disorders, the frequency of BAF subunit mutations is high. This underscores the rate-determining role of BAF complexes in neural development, homeostasis, and plasticity (Sony et al., 2014).
Diagnosis of CSS is based on both clinical features and molecular testing. The frequency of mutations in different genes in a study of 109 patients is as follows: ARID1B1 (65%), ARID1A (7%), SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%) and PHF6 (2%) (Kosho et al., 2014). The following flowchart outlines the diagnostic approach to a patient with clinically suspected CSS.
CSS is inherited in an autosomal dominant manner. Till date, all the pathogenic variants detected have been de novo mutations. If the pathogenic variant found in the proband is not detected in either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism. However, there has been no instance of germline mosaicism reported thus far in molecularly confirmed CSS patients. Prenatal testing for pregnancies at increased risk is possible after identifying the causative gene mutation. With the exception of one report of parental transmission, typically individuals with CSS do not reproduce.
Management of CSS is basically supportive. Occupational, physical and/or speech therapies are required to optimize developmental outcomes. Supplementation of nutrients and/or gastrostomy tube placement may be required to meet nutritional needs. Routine management of hearing loss and ophthalmologic abnormalities is required.
There is growing evidence for mutations in the BAF complex genes to be causal for CSS. The biology of BAF is very complicated and still remains unknown. According to recent studies SWI/SNF-mutant cancers depend on residual SWI/SNF complexes for their aberrant growth, revealing synthetic lethal interactions that could be used for therapeutic purposes. Certain cancers like small cell lung cancers and acute leukemias lack SWI/SNF mutations and are vulnerable to inhibition of the SWI/SNF ATPase subunit BRG1, whereas several other cell types do not show this sensitivity. There is emerging evidence that implicates SWI/SNF as a candidate drug target in human cancer.
Further research is required to reveal the importance of the SWI/SNF and BAF complex in human development, which could lead to the development of new targeted therapies for CSS in the future.
CSS is a heterogeneous disorder that can be diagnosed by clinical and molecular genetic testing. At present no definitive treatment is available. Therapies targeting the SWI/SNF pathway need further research.
1. Coffin GS, Siris E. Mental retardation with absent fifth fingernail and terminal phalanx. Am J Dis Child 1970; 119: 433-439.
2. Haspeslagh M et al. The Coffin-Siris syndrome: report of a family and further delineation. Clin Genet 1984; 26: 374–378.
3. Kosho T, et al., Coffin-Siris syndrome and related disorders involving components of the BAF (mSWI/SNF) complex: historical review and recent advances using next generation sequencing. Am J Med Genet C 2014; 166C: 241-251.
4. Kosho T et al. Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.Am J Med Genet C 2014; 166C: 262-275.
5. Santen GW, et al. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet 2012; 44: 379-380.
6. Santen GW, et al. SWI/SNF complex in disorder: SWItching from malignancies to intellectual disability. Epigenetics 2012; 7: 1219-1224.
7. Sony EY, et al. The role of BAF (mSWI/SNF) complexes in mammalian neural development.Am J Med Genet C 2014; 166C: 333-349.
8. Tang L et al. Structure and function of SWI/SNF chromatin remodeling complexes and mechanistic implications for transcription. Prog Biophys Mol Biol 2010; 102: 122-128.
9. Tsurusaki Y, et al. Coffin-Siris syndrome is a SWI/SNF complex disorder. Clin Genet 2014; 85: 548-554.
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